My guess is it’s actually quite a bit of evidence against any strong potential gains from updating, but weak evidence against weak gains.
So far, all talk of immune escape has mostly been exactly that, talk. That should make us wary of expecting it out of a new variant, or of updating too much from people’s concerns.
If a new variant comes along that does offer substantial escape from the vaccines, we will need to update the vaccines and get new versions out as quickly as possible. Will we be able to do that?
Technologically I have no worries. We’ll have that part solved within the week and probably within one day.
The problem here is original antigenic sin. Once you’ve been vaccinated against a particular variant, getting another vaccine for a very close relative generally won’t do anything other than reactivate the antibodies your body developed the first time around, rather than causing you to develop new antibodies specific to the new variant. Here is a study looking at this in the context of Covid vaccines, which does suggests some things we could do to mitigate the effect, but overall I think you shouldn’t expect vaccination against a specific variant to help all that much relative to just getting another wild-type booster.
So, independent of the fact that new, variant-specific vaccines not being produced is evidence that they wouldn’t help much, our prior should also be on them not helping much due to original antigenic sin (except for people who have yet to be vaccinated or infected at all). Original antigenic sin is a reason that, if some new variant does come along with significant vaccine escape—but which is still similar enough to the wild-type for original antigenic sin to apply—just developing new, variant-specific vaccines might not actually be an effective way out.
Experience from the IAV field indicates that multiple serial exposures to variant IAV strains might imprint (focus) the immune response to a narrow array of well-conserved viral epitopes relative to emerging subsequent strains and this might eventually reduce vaccine effectiveness. Randomizing multiple cohorts over time to either serial or partial immunization might also yield important neutralization data, although powering such studies for efficacy would be challenging. Larger observational studies of cohorts receiving serial immunizations might therefore also prove useful.
This suggests that it may be a good idea to avoid getting a booster now (with the ancestral spike protein) and wait for an Omicron-specific booster instead. (Use other precautions to avoid infection in the meantime.)
Although we believe it is likely that the current vaccines will continue to protect against severe disease caused by omicron, the possible need for a booster shot targeting a vaccine-resistant variant could be a reason to hold off for now on a booster targeting the original variant. For one thing, if omicron proves resistant to vaccine-induced protection against serious disease, then a booster dose with the current vaccine may not help. It’s also possible that repeatedly “training” the immune system to fight the original variant could reduce the effectiveness of a variant-specific booster. This phenomenon, called “original antigenic sin,” has been observed with influenza and human papillomavirus vaccines. In other words, for those not in immediate need of a boost, there may be a significant advantage to waiting until a booster more closely aligned with circulating variants becomes available; boosting on the original antigen could be counterproductive.
I don’t understand why you think that follows from that passage. I interpret it to mean serial exposure to a series of variant-specific vaccines may reduce overall effectiveness. e.g. Imagining a hypothetical variant sequence of V → V’ → V″. I interpret this as saying if you vaccinate for each with a variant-specific vaccine the effectiveness of the V″ vaccine will be less effective than the original vaccine was for V. Therefore they theorize it may be advantageous to break the chain and e.g. give half the people the V’ vaccine when available while the other half skips V’ and is given V″ vaccine when available.
Their reasoning isn’t entirely clear to me since it’s not clear to me exactly how and by what mechanism(s) the vaccine effectiveness may degrade.
So… if the vaccine is for the s2 subunit, and Delta had one s2 change that dropped effectiveness enough for breakthroughs, then eight more s2 changes will probably be a lot worse in terms of dropping vaccine effectiveness.
Are there any biology types that can tell me how accurate/crazy this reasoning is?
I believe the mRNA vaccines are based on the full-length spike protein, not just the S2 subunit. The S1 subunit includes the critical receptor binding domain, which is a common target of neutralizing antibodies induced by vaccination, and is the location of many further mutations seen in Omicron.
Edit: To be clear, this fact doesn’t invalidate your point about the new mutations looking possibly quite bad for vaccine efficacy.
From the early stages of COVID-19 vaccine development, scientists sought to target a SARS-CoV-2 protein that was least likely to cause ADE. For example, when they found out that targeting the nucleoprotein of SARS-CoV-2 might cause ADE, they quickly abandoned that approach. The safest route seemed to be targeting the S2 subunit of the spike protein, and they ran with that, wrote Derek Lowe, PhD, in his Science Translational Medicine blog “In the Pipeline.”
Following your link and looking for the original source, I found that actually Derek Lowe appears not to say that in his blog post, as least not anymore (he made an edit there—though it is not clear that it ever mentioned the S2 subunit).
Specifically, it was the vaccines that targeted the N (nucleoprotein) antigen of the coronavirus that had ADE problems, while the ones that targeted the S (Spike) protein did not. Update: this isn’t accurate. There was trouble after immunization with a nucleoprotein-directed vaccine, but ADE could also be seen with some of the Spike-directed vaccine candidates as well—see reviews here, here, and here.
Anyway, it is possible for us to independently see from many different sources that the vaccines code for full-length spike (with minor modification to stabilize the naturally somewhat “floppy” protein in the desired “prefusion” configuration). For example, from here (https://www.nejm.org/doi/full/10.1056/nejmoa2035389):
The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Announcing it might have meant that people who wait to get vaccinated till the new version arrives get better protection which is a message that the people at the CDC hate to tell people.
That might be enough to push the institutions into a state where they won’t develop a slightly better vaccine that doesn’t add much when it might make people more skeptical of taking the current one?
Yes, at least that’s also my understanding—especially since we are still vaccinating new people, not just giving out boosters. My point is just that it seems like we shouldn’t rely on updated vaccines being able to change the course of the pandemic in a major way.
Thanks for providing this, it seems extremely important for trying to predict how the pandemic will play out. So we should have been much more scared of COVID variants than we would be absent original antigentic sin. As it was predictable that COVID, because it was new to humans, would mutate this means those, including myself, who had never heard of this force likely underestimated the expected harm of COVID. Why wasn’t this something that the official experts were talking about long ago?
Is original antigenic sin widely accepted? It’s not clear to me that there’s a strong consensus based on your link.
EDIT:
I did a bit of (not very thorough) googling on original antigenic sin, and managed to convince myself that, yes, it’s a thing. But then to help myself sleep I looked up “overcoming original antigenic sin” and came across this:
My uninformed impression is that an “adjuvant” is just something that stimulates increased immune response, which has historically been an additional chemical (such as an aluminum salt) added to vaccines. The mRNA vaccines do not contain these chemicals, but some people confusingly refer to the lipid nanoparticles that surround and protect the mRNA as adjuvants (because they also help increase immune response). I haven’t seen any evidence that these lipid nanoparticles are the kind of adjuvants that might mitigate OAS, but that doesn’t mean much because I’m a total nonexpert.
Adjuvants are for activating the immune system to respond to free-floating virus particles. If the virus actually infects a cell and produces proteins on the cell’s surface, that is a different signal to the immune system and adjuvants are not needed. Thus adjuvants were not needed for traditional live/attenuated vaccines and 21st century mRNA and vector vaccines (AZ, etc), but were needed for 1980s recombinant protein vaccines (Novavax) and traditional dead/inactivated vaccines.
Immune response to the lipid nanoparticles themselves is very bad. It reduces the uptake of protein coding mRNA into the cells and diminishes vaccine efficacy. It also leads to most of the severe allergic reactions.
How does Original Antigenic Sin work for natural immunity vs vaccine derived immunity? Is it a stronger impediment for one vs the other?
Also, this whole topic seems (I think) to be mostly independent of the T-cell immunity that gives you the baseline immunity to severe disease—the reason for Zvi’s low estimate of full immune escape, I think.
This doesn’t directly answer your question but it appears that people who received mRNA vaccines produced fewer antibodies for one of the four endemic coronaviruses than those who were naturally infected. If that’s true, it’s very encouraging news as far as adapting vaccines is concerned:
Regarding the link: Possibly you did not activate the markdown editor for your profile? In that case you can create one by marking the link-text: a hover-menu will appear with the option to add a link
The link is working for me, though the markdown you used isn’t formatting the way it is supposed to.
So if I understand correctly, Moderna gave a third dose of either the B.1.351 variant shot or the original 1273 shot to patients and found that those given the B.1.351 shot had higher levels of neutralizing antibodies against the variant?
This seems to suggest that we could do strain specific boosters against COVID. I suspect that would be particularly true for Omicron since it has so much more antigenic drift than the other variants.
An alternate interpretation of the result is that Beta just didn’t have much immune escape. That fact that it was crushed by Delta suggests that. The vaccine produced antibodies that were more tuned to Beta than those from the original vaccine, but the difference was slight, just a factor of 2. We won’t know about OAS until we have a variant with real immune escape, which may well be Omicron. But I’m not worried about OAS because it’s a lower order effect.
FWIW, there is other SARS2-specific supporting evidence that immune imprinting may be an issue for vaccine updates. Lately in the UK Health Security Agency weekly vaccine surveillance reports they have begun including this note:
>(iii) recent observations from UK Health Security Agency (UKHSA) surveillance data that N antibody levels appear to be lower in individuals who acquire infection following 2 doses of vaccination.
The UK tracks seropositivity of S and N antibodies. N antibody positivity is used to track the subset of people who were previously infected. This note implies the immune system may not be updating its response when challenged with a new variant of the live virus.
The problem here is original antigenic sin. Once you’ve been vaccinated against a particular variant, getting another vaccine for a very close relative generally won’t do anything other than reactivate the antibodies your body developed the first time around, rather than causing you to develop new antibodies specific to the new variant. Here is a study looking at this in the context of Covid vaccines, which does suggests some things we could do to mitigate the effect, but overall I think you shouldn’t expect vaccination against a specific variant to help all that much relative to just getting another wild-type booster.
So, independent of the fact that new, variant-specific vaccines not being produced is evidence that they wouldn’t help much, our prior should also be on them not helping much due to original antigenic sin (except for people who have yet to be vaccinated or infected at all). Original antigenic sin is a reason that, if some new variant does come along with significant vaccine escape—but which is still similar enough to the wild-type for original antigenic sin to apply—just developing new, variant-specific vaccines might not actually be an effective way out.
From your linked paper https://www.cell.com/trends/immunology/fulltext/S1471-4906(21)00177-0:
This suggests that it may be a good idea to avoid getting a booster now (with the ancestral spike protein) and wait for an Omicron-specific booster instead. (Use other precautions to avoid infection in the meantime.)
A trio of vaccine experts made the same point in https://www.washingtonpost.com/outlook/2021/11/29/booster-shots-universal-opinion/:
I don’t understand why you think that follows from that passage. I interpret it to mean serial exposure to a series of variant-specific vaccines may reduce overall effectiveness. e.g. Imagining a hypothetical variant sequence of V → V’ → V″. I interpret this as saying if you vaccinate for each with a variant-specific vaccine the effectiveness of the V″ vaccine will be less effective than the original vaccine was for V. Therefore they theorize it may be advantageous to break the chain and e.g. give half the people the V’ vaccine when available while the other half skips V’ and is given V″ vaccine when available.
Their reasoning isn’t entirely clear to me since it’s not clear to me exactly how and by what mechanism(s) the vaccine effectiveness may degrade.
Vaccine is for the S2 subunit. If I’m reading this correctly the subunit is 686–1273 residues. https://www.nature.com/articles/s41401-020-0485-4
I had previously read that delta had one mutation there and the vaccines still held up pretty well. It looks like Wikipedia agrees, and that would be D950N. https://en.wikipedia.org/wiki/SARS-CoV-2_Delta_variant#Mutations
Looking at the 686-1273 mutations for Omicron in the s2 subunit, it looks like there’s a lot more (9 if the article is correct so far) N764K, D796Y, N856K, Q954H, N969K, L981F, V1069I, Δ1265, L1266I https://en.wikipedia.org/wiki/SARS-CoV-2_Omicron_variant#Mutations
So… if the vaccine is for the s2 subunit, and Delta had one s2 change that dropped effectiveness enough for breakthroughs, then eight more s2 changes will probably be a lot worse in terms of dropping vaccine effectiveness.
Are there any biology types that can tell me how accurate/crazy this reasoning is?
I believe the mRNA vaccines are based on the full-length spike protein, not just the S2 subunit. The S1 subunit includes the critical receptor binding domain, which is a common target of neutralizing antibodies induced by vaccination, and is the location of many further mutations seen in Omicron.
Edit: To be clear, this fact doesn’t invalidate your point about the new mutations looking possibly quite bad for vaccine efficacy.
I’m pretty certain on this point as it was related to discussion a few months ago about antibody dependent enhancement. Vaccines targeted the s2 subunit as it was thought to be the least likely to create ADE and also the slowest to mutate. https://www.lesswrong.com/posts/5yarKt4MqRjv72mYv/covid-8-26-full-vaccine-approval?commentId=Dwuyzup535CaGEJ4b
As quoted in that post:
Following your link and looking for the original source, I found that actually Derek Lowe appears not to say that in his blog post, as least not anymore (he made an edit there—though it is not clear that it ever mentioned the S2 subunit).
https://www.science.org/content/blog-post/antibody-dependent-enhancement-and-coronavirus-vaccines
Anyway, it is possible for us to independently see from many different sources that the vaccines code for full-length spike (with minor modification to stabilize the naturally somewhat “floppy” protein in the desired “prefusion” configuration). For example, from here (https://www.nejm.org/doi/full/10.1056/nejmoa2035389):
Also, the S1 subunit is that part that contains the receptor binding domain, and it is possible to read in many papers (e.g. https://www.science.org/doi/10.1126/scitranslmed.abi9915) that the vaccines elicit antibodies that target this domain.
It looks liken you’re right. Thanks for checking here.
Presumably we still should have shifted everything over anyway, it’s a freeroll that can only help?
Announcing it might have meant that people who wait to get vaccinated till the new version arrives get better protection which is a message that the people at the CDC hate to tell people.
That might be enough to push the institutions into a state where they won’t develop a slightly better vaccine that doesn’t add much when it might make people more skeptical of taking the current one?
Yes, at least that’s also my understanding—especially since we are still vaccinating new people, not just giving out boosters. My point is just that it seems like we shouldn’t rely on updated vaccines being able to change the course of the pandemic in a major way.
Thanks for providing this, it seems extremely important for trying to predict how the pandemic will play out. So we should have been much more scared of COVID variants than we would be absent original antigentic sin. As it was predictable that COVID, because it was new to humans, would mutate this means those, including myself, who had never heard of this force likely underestimated the expected harm of COVID. Why wasn’t this something that the official experts were talking about long ago?
Probably for the same reason they downplayed the drop in vaccine efficacy from Delta: they didn’t want to increase vaccine hesitancy.
We weren’t the official experts talking about airborne transmission long ago?
Is original antigenic sin widely accepted? It’s not clear to me that there’s a strong consensus based on your link.
EDIT:
I did a bit of (not very thorough) googling on original antigenic sin, and managed to convince myself that, yes, it’s a thing. But then to help myself sleep I looked up “overcoming original antigenic sin” and came across this:
https://news.emory.edu/stories/2012/08/flu_vaccines_original_sin/campus.html
Adjuvants! I really have no idea what they are, but I seem to remember that these are added to all the covid vaccine?
My uninformed impression is that an “adjuvant” is just something that stimulates increased immune response, which has historically been an additional chemical (such as an aluminum salt) added to vaccines. The mRNA vaccines do not contain these chemicals, but some people confusingly refer to the lipid nanoparticles that surround and protect the mRNA as adjuvants (because they also help increase immune response). I haven’t seen any evidence that these lipid nanoparticles are the kind of adjuvants that might mitigate OAS, but that doesn’t mean much because I’m a total nonexpert.
Adjuvants are for activating the immune system to respond to free-floating virus particles. If the virus actually infects a cell and produces proteins on the cell’s surface, that is a different signal to the immune system and adjuvants are not needed. Thus adjuvants were not needed for traditional live/attenuated vaccines and 21st century mRNA and vector vaccines (AZ, etc), but were needed for 1980s recombinant protein vaccines (Novavax) and traditional dead/inactivated vaccines.
Immune response to the lipid nanoparticles themselves is very bad. It reduces the uptake of protein coding mRNA into the cells and diminishes vaccine efficacy. It also leads to most of the severe allergic reactions.
How does Original Antigenic Sin work for natural immunity vs vaccine derived immunity? Is it a stronger impediment for one vs the other?
Also, this whole topic seems (I think) to be mostly independent of the T-cell immunity that gives you the baseline immunity to severe disease—the reason for Zvi’s low estimate of full immune escape, I think.
This doesn’t directly answer your question but it appears that people who received mRNA vaccines produced fewer antibodies for one of the four endemic coronaviruses than those who were naturally infected. If that’s true, it’s very encouraging news as far as adapting vaccines is concerned:
https://www.medrxiv.org/content/10.1101/2021.09.30.21264363v1
There’s this post, which suggests that Original antigenic sin is unlikely to be a problem. I really hope that’s true.
Regarding the link: Possibly you did not activate the markdown editor for your profile?
In that case you can create one by marking the link-text: a hover-menu will appear with the option to add a link
Thank you, I had no idea markdown needed to be actively activated in the profile.
The link is working for me, though the markdown you used isn’t formatting the way it is supposed to.
So if I understand correctly, Moderna gave a third dose of either the B.1.351 variant shot or the original 1273 shot to patients and found that those given the B.1.351 shot had higher levels of neutralizing antibodies against the variant?
This seems to suggest that we could do strain specific boosters against COVID. I suspect that would be particularly true for Omicron since it has so much more antigenic drift than the other variants.
An alternate interpretation of the result is that Beta just didn’t have much immune escape. That fact that it was crushed by Delta suggests that. The vaccine produced antibodies that were more tuned to Beta than those from the original vaccine, but the difference was slight, just a factor of 2. We won’t know about OAS until we have a variant with real immune escape, which may well be Omicron. But I’m not worried about OAS because it’s a lower order effect.
FWIW, there is other SARS2-specific supporting evidence that immune imprinting may be an issue for vaccine updates. Lately in the UK Health Security Agency weekly vaccine surveillance reports they have begun including this note:
>(iii) recent observations from UK Health Security Agency (UKHSA) surveillance data that N antibody levels appear to be lower in individuals who acquire infection following 2 doses of vaccination.
(From page 39 paragraph 3 of https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1036047/Vaccine_surveillance_report_-_week_47.pdf)
The UK tracks seropositivity of S and N antibodies. N antibody positivity is used to track the subset of people who were previously infected. This note implies the immune system may not be updating its response when challenged with a new variant of the live virus.